Autoregulation is the intrinsic ability of an organ to maintain a relatively constant blood flow over a range of perfusion pressures via local active changes in vascular resistance to flow. All previous work on autoregulation of skeletal muscle blood flow has been performed in anesthetized animals. Therefore, the main objectives of this research are to determine conditions that allow the expression of autoregulatory behavior and to evaluate quantitatively the efficiency of autoregulation (i.e., closed-loop gain of flow regulation) during these conditions in the hindlimb vascular bed of conscious dogs. Specifically, we will test the hypothesis that the efficiency of autoregulation of hindlimb blood flow is directly related to the level of tissue metabolism. Dogs will be studied while at rest and during increases in hindlimb oxygen consumption produced by 1) treadmill exercise and 2) pretreatment with 2,4-dinitrophenol. We will also evaluate the role of adenosine as a possible mediator of autoregulation and examine the possible influences of the autonomic nervous system upon hindlimb blood flow autoregulation in conscious dogs. Autoregulatory efficiency will be quantitated from an analysis of hindlimb pressure-flow (P-F) relationships. Three techniques will be used to study the hindlimb P-F relationship: 1) regulation of hindlimb perfusion pressure with an occlusion cuff while measuring flow, 2) controlled flow perfusion via a roller pump while measuring perfusion pressure, and 3) controlled pressure perfusion while measuring flow. The last two techniques are extracorporeal bypass techniques developed by us that allow exploration of hindlimb P-F relationships over wide ranges of pressure and flow in conscious dogs. The importance of understanding blood flow autoregulation stems from the concept that it is one of the mechanisms that operates to match nutrient delivery with tissue metabolic demands. Also, autoregulatory-mediated increases in total peripheral resistance have been suggested to occur inboth clinical and experimental forms of hypertension. Our proposed experiments will provide fundamental new information concerning the operation of autoregulation in the hindlimb vascular bed of normal dogs and lead us closer to being able to evaluate autoregulation during the development of renovascular hypertension in conscious dogs.